Process for the cis-selective catalytic hydrogenation of...

Details Process for the cis-selective catalytic hydrogenation of... Process for the cis-selective catalytic hydrogenation of...

2002-01-25

2004-04-13

Nazario-Gonzalez, Porfirio (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

Reexamination Certificate

active

06720454

ABSTRACT:

The invention relates to a process for the cis-selective catalytic hydrogenation of cyclohexylidenamines and their precursors.
Cyclohexylamines can be used, inter alia, as antioxidants and as active ingredients in pharmaceuticals. An important cyclohexylamine is sertraline:
Sertraline: (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthylamine, cf.
Merck Index Twelfth Edition
1996, No. 8612 is known as an antidepressant. The preparation of this compound is described in U.S. Pat. No. 4,536,518. The hydrochloride is commercially available, inter alia, under the trade names Lustral® and Zoloft®. Cyclohexylamines of the type:
(R
2
≠H) exist in at least two isomeric forms:
In the case of further, asymmetric substitution on the cyclohexyl ring, the carbon atoms in the 1 and 4 positions are chiral. According to the R,S nomenclature of Kahn, Ingold and Prelog, sertralin has the 1S, 4S configuration.
Cyclohexylamines are obtained, for example, by the following method: reaction of the ketone:
with a primary amine, e.g. methylamine, results in elimination of water to give a cyclohexylidenamine:
The imine formed is subsequently catalytically hydrogenated to give the amine. Such reactions proceed in only a low stereoselectivity, if any. In the case of sertralin, four enantiomers are obtained.
It is an object of the present invention to prepare cyclohexylamines containing a very high proportion of cis-isomers.
To achieve the object, the abovementioned U.S. Pat. No. 4,536,518, for example, proposes hydrogenating an imine of the formula:
using palladium on carbon as support. This gives 70% of cis-racemate and 30% of trans-racemate.
To improve this yield further, WO 93/01161 proposes using Raney nickel as catalyst in place of palladium on carbon as support for the hydrogenation of the imine. This gives a cis/trans ratio of 8:1.
It has now surprisingly been found that an even better cis/trans ratio is obtained when the imine is hydrogenated in the presence of a copper-containing catalyst and in the presence of a protic solvent. Although the preparation of secondary amines from ketones and intermediate imines by hydrogenation in the presence of copper chromite catalysts is known from R. B. C. Pillai
J. Mol. Catalysis
84 (1993), 125-129, it is surprising that when starting from cyclohexylidenamines, which can also be formed as intermediates from ketones, the hydrogenation using a copper-containing catalyst proceeds diastereoselectively and gives a high proportion (>95%) of cis isomers.
The invention provides a process for preparing cis compounds of the formula:
in which R
1
and R
2
are, independently of one another, hydrocarbon radicals and A are substituents and m is an integer from 0 to 4 which defines the number of substituents A, which comprises
a) hydrogenating a cyclohexylidenamine of the formula:
in which n is zero or 1, R
1
, R
2
, A and m are as defined above, in the presence of a copper-containing catalyst and in the presence of a protic solvent; or
b) reacting a ketone of the formula:
in which R
2
, A and m are as defined above, with a compound which introduces the group R
1
—N→(O)
n
, hydrogenating the imine or nitrone (II) obtainable as an intermediate in the presence of a copper-containing catalyst and in the presence of a protic solvent and isolating the cis compound (I).
When m is zero and the cyclohexyl ring is unsubstituted in a compound (I), the two structural formulae represent identical compounds:
In the description of the present invention, the structural formula of the cis compound (I) of both possibilities is represented using only the formula:
When m is from 1 to 4 (m>0) and the cyclohexyl ring is unsymmetrically substituted in a compound (1), the hydrogenation selectively gives a cis enantiomer pair which can be separated into the optically pure enantiomers by customary methods of racemate resolution, for example by crystallization of the mandelic acid salt using the method of W. M. Welch et al in
J. Med. Chem
. 1984, 27, 1508-1515. The relationship between the two cis and trans enantiomer pairs and the four optically pure enantiomers is illustrated by the following formulae for sertralin:
In the structural formulae of the starting materials (II) and (III), the uniform-thickness bonds to the substituent R
2
indicate that in the case of R
2
≠H and different substitution on the cyclohexyl ring, these starting materials can be used in the process in the form of racemic mixtures having equal or different proportions of the enantiomers or in the form of an optically pure enantiomer.
The process gives a high yield of desired cis compounds. In the case of the synthesis of sertralin, a ratio of the cis enantiomer pair to the trans enantiomer pair of greater than 95:5 is obtained. In a particularly preferred embodiment, the even better ratio of greater than 99:1 is achieved. This high yield of cis compounds also eliminates the separation of the cis enantiomer pair from the trans enantiomer pair which is otherwise necessary in the presence of different substituents A (m>0).
The definitions and designations used in the description of the present invention preferably have the following meanings:
A hydrocarbon radical R
1
or R
2
is selected, in particular, from the group consisting of C
1
-C
20
alkyl, C
4
-C
12
cycloalkyl, C
2
-C
11
heterocycloalkyl, carbocyclic C
5
-C
16
aryl, C
2
-C
15
heteroaryl, carbocyclic C
7
-C
16
aralkyl and C
2
-C
15
heteroarylalkyl and can additionally be substituted by a suitable functional group, e.g. selected from the group of functional groups or derivatized functional groups consisting of amino, C
1
-C
4
alkylamino, C
1
-C
4
dialkylamino, hydroxy, carboxy and halogen.
The cyclohexyl ring can be substituted by from one to four, preferably two, substituents selected from the group A consisting of the substituents R
3
, R
4
, R
5
and R
6
. Suitable substituents are listed in the List of Radical Names under the IUPAC Rules and remain unchanged under the conditions of the catalytic hydrogenation reaction. The substituents may be chosen freely. Suitable substituents A from the group R
3
, R
4
, R
5
and R
6
are, for example, selected from the group of functional groups or derivatized functional groups consisting of amino, C
1
-C
4
alkylamino, C
1
-C
4
dialkylamino, hydroxy, carboxy and halogen or are saturated aliphatic, cycloaliphatic or heterocycloaliphatic radicals, carbocyclic or heterocyclic aryl radicals, fused carbocyclic, heterocyclic or carbocyclic-heterocyclic radicals, which may in turn be combined in any way with further radicals of this group and can be substituted by the functional groups or derivatized functional groups mentioned.
The abovementioned substituents and radicals can also be interrupted by one or more divalent radicals selected from the group consisting of —O—, —C(═O)—O—, —O—C(═O)—, —C(═O)—N(C
1
-C
4
alkyl)-, —N(C
1
-C
4
alkyl)-C(═O)—, —S(═O)
2
—, —S(═O)
2
—O—, —O—S(═O)
2
—, —S(═O)
2
—N(C
1
-C
4
alkyl)-, —(C
1
-C
4
alkyl)N—S(═O)
2
—, —P(═O)—, —P(═O)—O—, —O—P(═O)— and —O—P(═O)—O—.
In a preferred embodiment, two substituents A from the group R
3
, R
4
, R
5
and R
6
form divalent, bridging C
2
-C
6
alkylene, C
4
-C
8
alkyldiylidene or C
4
-C
8
alkenyidiylidene groups, preferably butanediylidene, in particular 2-butenediylidene which is joined to the cyclohexyl ring at two adjacent carbon atoms and together with these carbon atoms forms a phenyl ring which may be substitued by the abovementioned functional groups or substituents.
Further suitable substituents A from the group R
3
, R
4
, R
5
and R
6
are substituents selected from the group consisting of C
1
-C
20
alkyl, C
4
-C
12
cycloalkyl, C
7
-C
12
bicycloalkyl, C
2
-C
11
hetero-cycloalkyl, carbocyclic C
6
-C
16
aryl, C
2
-C
15
heteroaryl, carbocyclic C
7
-C
16
aralkyl and C
2
-C
15
heteroarylalkyl, which may in turn be substituted by the abovementioned functional groups and interrupted by divalent radicals.
Examples of C
1
-C
20
alkyl are methyl, ethyl, n

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